These experiments are designed to determine whether adolescents at risk for substance abuse (SA) exhibit impaired cognitive performance on a task that reveals a deficit in performance by adults with a history of SA. Abnormal cognitive performance in adults after long-term exposure to drugs of abuse can reflect either vulnerability to SA (primary effect) or drug effects on the brain (secondary effect). This study tests the hypothesis that a predisposing cognitive deficit in adolescents contributes to risk for substance abuse. To date, 57 adolescents completed the initial phase of the study and six have completed their 3-year follow-up visit. Adolescents at risk for SA showed worse performance on a Gambling task (GT), which targets impulsivity and judgment and depends on orbitofrontal cortical function, and on the Wisconsin Card Sorting Task (WCST), which targets executive function and activates the dorsolateral prefrontal cortex in healthy control subjects. Task performance on the WCST was correlated predominantly with global functioning, a measure of psychiatric symptom severity, and performance on the GT correlated with antisocial and aggressive behaviors. Although both tasks differentiated adolescents at risk from controls, the WCST may be less specific to a neurobiological vulnerability for substance abuse because it relates more to psychiatric status. In contrast, the GT task may be more relevant for substance abuse problems as it is influenced by aggressive and antisocial behaviors, which are known to predict later substance abuse. These results are preliminary and await confirmation by studying larger samples, and assessing directly the significance of the findings in follow-up data.